Correlation of functional and ultrastructural abnormalities of mitochondria in mouse heart carrying a pathogenic mutant mtDNA with a 4696-bp deletion.

We examined the correlation of functional and structural abnormalities of cardiac mitochondria created by pathogenic mutant mtDNAs using mito-mice with hearts carrying 88% mutant DeltamtDNA4696 with a 4696 deletion. COX histochemistry, quantitative PCR analysis, and electronmicrographs showed that accumulation of 91.6% DeltamtDNA4696 in single cardiac muscle fibers induced progressive reduction of COX activity to form COX-negative fibers.

Oculopharyngodistal myopathy is genetically heterogeneous and most cases are distinct from oculopharyngeal muscular dystrophy.

The question whether oculopharyngodistal myopathy (MIM 164310) is a distinct disease entity or a variant of oculopharyngeal muscular dystrophy (MIM 164300) persists. To answer this question, we examined five patients with the clinical characteristics of oculopharyngodistal myopathy for GCG expansion in poly(A)-binding protein nuclear 1 gene (previously called poly(A)-binding protein 2), the causative gene defect for oculopharyngeal muscular dystrophy. Only one of our five patients had the significant GCG expansion.

Infantile autophagic vacuolar myopathy is distinct from Danon disease.

Lysosomal glycogen storage disease with normal acid maltase (Danon) is caused by primary lysosome-associated membrane protein-2 (LAMP-2) deficiency. Typically, the disease begins after the first decade; however, two infantile patients had similar histologic features. The infantile disorder is distinct from Danon disease, because, in both infants, LAMP-2 protein is present in skeletal muscle.

The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle.

Dysferlin is a surface membrane protein in skeletal muscle whose deficiency causes distal and proximal, recessively inherited, forms of muscular dystrophy designated Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B), respectively. The function of dysferlin is not defined. Caveolin-3 is another skeletal muscle membrane protein which is important in the formation of caveolae and whose mutations cause dominantly inherited limb girdle muscular dystrophy type 1C (LGMD1C).

Calpain 3 gene mutations: genetic and clinico-pathologic findings in limb-girdle muscular dystrophy.

Mutations in the calpain 3 gene have been proven to be responsible for limb-girdle muscular dystrophy (LGMD) type 2A. To determine the incidence and genotypes of the calpain 3 (p94) gene mutations in Japanese LGMD patients, we sequenced the gene in 80 patients with clinical characteristics of autosomal recessive or sporadic LGMD. We identified 13 distinct pathogenic mutations in 21 patients (26%), including seven missense mutations, four splice-site mutations and two insertions in which six were novel mutations.

The significance of type 1 fiber atrophy (hypotrophy) in childhood neuromuscular disorders.

To determine the incidence of selective type 1 fiber atrophy (hypotrophy) and its possible significance in various muscle diseases of childhood, we reviewed 2212 muscle biopsies from children which we had examined in the past 20 years histochemically with ATPase staining. Type 1 fiber atrophy was seen in a variety of neuromuscular disorders, but predominantly in congenital myopathies, including all patients with congenital fiber type disproportion myopathy (20 patients), central core disease (12 patients) and multicore disease (four patients). Although type 1 fiber atrophy was not a constant feature in nemaline myopathy and myotubular myopathy, all patients with these diseases had abnormal fiber type distribution which included type 1 fiber predominance both with and without type 2B fiber deficiency.

Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA.

Here we investigated the pathogenesis of deletion mutant mitochondrial (mt)DNA by generating mice with mutant mtDNA carrying a 4696-basepair deletion (DeltamtDNA4696), and by using cytochrome c oxidase (COX) electron micrographs to identify COX activity at the individual mitochondrial level. All mitochondria in tissues with DeltamtDNA4696 showed normal COX activity until DeltamtDNA4696 accumulated predominantly; this prevented mice from expressing disease phenotypes. Moreover, we did not observe coexistence of COX-positive and -negative mitochondria within single cells.

Schwann cell myelination occurred without basal lamina formation in laminin alpha2 chain-null mutant (dy3K/dy3K) mice.

The laminin alpha2 chain is a major component of basal lamina in both skeletal muscle and the peripheral nervous system. Laminin alpha2 chain deficiency causes merosin-deficient congenital muscular dystrophy, which affects not only skeletal muscles, but also the peripheral and central nervous systems. It has been reported that the formation of basal lamina is required for myelination in the peripheral nervous system.

Selective deficiency of alpha-dystroglycan in Fukuyama-type congenital muscular dystrophy.

Background: Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive disorder characterized by severe dystrophic muscle wasting from birth or early infancy with structural brain abnormalities. The gene for FCMD is located on chromosome 9q31, and encodes a novel protein named fukutin. The function of fukutin is not known yet, but is suggested to be an enzyme that modifies the cell-surface glycoprotein or glycolipids.

Muscle plasma membrane changes in dystrophin gene exon 52 knockout mouse.

Changes in muscle plasma membranes in mice lacking exon 52 of the dystrophin gene (mdx52 mouse) were studied using the freeze-fracture technique. The extensor digitorum longus (EDL) muscle plasma membrane of the mdx52 mouse at 8 weeks of age showed significantly increased caveola density (p < 0.05 by two-tailed t-test) and significantly decreased densities of intramembranous particles (IMPs), orthogonal arrays (OAs) and orthogonal array subunit particles (OASPs) (p < 0.

A mitochondrial encephalo-myo-neuropathy with a nucleotide position 3271 (T-C) point mutation in the mitochondrial DNA.

We report three members of a family, who exhibited a phenotype similar to 'myoclonus epilepsy with ragged-red fibers' but had a genotype usually associated with 'mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes'. The patients, a 48-year-old female, and her two sons, aged 21 and 19 respectively, presented with photo-reactive syncopal episodes, disturbances of gait and writing, dysarthria and finger tremor since the 3rd and 2nd decade of life, respectively, that were accompanied also by numbness and weakness of the extremities. Subsequently, cerebellar ataxia and myoclonus were also noted.

Maximal and submaximal forces of slow fibers in human soleus after bed rest.

The effects of 2 and 4 mo of bed rest, with or without exercise countermeasures, on the contractile properties of slow fibers in the human soleus muscle were examined. Mean fiber diameters were 8 and 36% smaller after 2 and 4 mo of bed rest, respectively, than the pre-bed rest level. Maximum tetanic force (P(o)), maximum activated force (F(max)) per cross-sectional area (CSA), and the common-logarithm value of free Ca(2+) concentration required for half-maximal activation (pCa(50)) also decreased after 2 and 4 mo of bed rest.

Massive muscle cell degeneration in the early stage of merosin-deficient congenital muscular dystrophy.

Primary merosin-deficient congenital muscular dystrophy (CMD) is a severe form of congenital muscular disorder which is caused by mutations in the laminin alpha2 chain gene (LAMA2). The disease is characterized by marked dystrophic changes in skeletal muscles during early infancy, while little is known about the pathological process of the muscle fiber degeneration. Here, we report the immunohistochemical analysis of skeletal muscle in ten patients with primary merosin-deficient CMD using a panel of molecular markers for skeletal muscle proteins, cellular necrosis, and apoptosis.

Sarcolemmopathy: muscular dystrophies with cell membrane defects.

In this article, we review the molecular pathology of muscular dystrophies caused by defects of proteins located within or near cell membranes. These disorders include Bethlem myopathy, merosinopathy, dystrophinopathy, sarcoglycanopathies, integrinopathy, dysferlinopathy and caveolinopathy. We refer to these diseases collectively as sarcolemmopathy.

A case of MERRF associated with chronic pancreatitis.

We report the first case to our knowledge of chronic pancreatitis associated with mitochondrial encephalopathy with the A8344G mitochondrial DNA (mtDNA) mutation. This 10-year-old-girl had suffered from recurrent abdominal pain with elevated serum amylase and lipase since the age of 6, and easy fatigability, tremor and astatic seizures since the age of 8. A biopsy of quadriceps muscle revealed ragged-red-fibers and cytochrome c oxidase deficiency.

[Overloading to neck extensor muscles is an aggravating factor to induce further neck drop in isolated neck extensor myopathy (Katz). A case report].

A 78-year-old woman was hospitalized because of progressive anterior neck drop over 4 months prior to admission. She was normal except for mild weakness of her neck, trapezius and biceps brachii muscles. EMG revealed mild myopathic changes in the neck extensors, trapezius, deltoid and sternocleidomastoid muscles.

[Muscle involvement of Stormorken's syndrome].

We described two patients, a mother and daughter, of Stormorken's syndrome. The syndrome is characterized clinically by autosomal dominant inheritance, congenital miosis, thrombocytopenia, asplenia and muscle weakness. Both patients had bleeding tendency, ichthyosis of arms, and muscle weakness.

Ontogenetic, gravity-dependent development of rat soleus muscle.

We tested the hypothesis that rat soleus muscle fiber growth and changes in myosin phenotype during the postnatal, preweaning period would be largely independent of weight bearing. The hindlimbs of one group of pups were unloaded intermittently from postnatal day 4 to day 21: the pups were isolated from the dam for 5 h during unloading and returned for nursing for 1 h. Control pups were either maintained with the dam as normal or put on an alternating feeding schedule as described above.